Preclinical (1)H-MRS neurochemical profiling in neurological and psychiatric disorders

Abstract

The ongoing development of animal models of neurological and psychiatric disorders in combination with the development of advanced nuclear magnetic resonance (NMR) techniques and instrumentation has led to increased use of in vivo proton NMR spectroscopy ((1)H-MRS) for neurochemical analyses. (1)H-MRS is one of only a few analytical methods that can assay in vivo and longitudinal neurochemical changes associated with neurological and psychiatric diseases, with the added advantage of being a technique that can be utilized in both preclinical and clinical studies. In this review, recent progress in the use of (1)H-MRS to investigate animal models of neurological and psychiatric disorders is summarized with examples from the literature and our own work.

Figure 1. Comparison of ¹H-NMR spectra recorded at 7 T (300 MHz) and 16.4 T (700 MHz)

All spectra are recorded from the 2 mm × 2 mm × 2 mm voxel using PRESS at 37°C with TE 10 ms, TR 2 s and NA 512; (A) spectra from a 0.5% agar gel phantom sample with Cr, GABA, NAA and Glu (50 mM each); Ins and Gln (25 mM each); and, Cho and Tau (10 mM each). Both spectra are shimmed to approximately 3 Hz. When presented on the same ppm scale, lines in the 700 MHz spectrum are narrower (7/3-times). At constant line width the sensitivity improves with the field strength, in our example about 2.7-times. For the same reason, multiplets in the 700 MHz spectrum look narrower. Multiplet narrowing generally increases apparent line separation across the spectrum. The Glu/GABA overlapping triplets at 2.3 ppm (green bar) are completely resolved at 700 MHz. (B) The 300 MHz in vivo spectra of mouse brain and the phantom from (A). To guide the eye, the phantom spectrum is line broadened by LB 20 Hz. It is obvious that the in vivo spectrum resembles the line-broadened phantom spectrum. (C) The 700 MHz in vivo spectrum, at the same apparent line width is much better resolved. Notable is separation of Glu/GABA lines at 2.3 ppm, which were otherwise unresolved at 7 T. Cho: Choline; Cr: Creatine; GABA: γ-aminobutyric acid; Gln: Glutamine; Glu: Glutamate; GPC+PCh: Choline-containing compounds; Gua: Guanosine; Ins: myo-inositol; Lac: Lactate; NAA: N-acetylaspartate; PCr: Phosphocreatine; Tau: Taurine.

Figure 2. Metabolite quantification of the mouse nucleus accumbens using in vivo 16.4 T MRS and LCModel

(A) Representative RARE images of 1.0 mm thick coronal and sagittal brain sections where the 8 μl VOI is centered on th1e nucleus accumbens. Scale bar = 2 mm. (B) Location of the voxel on a cartoon coronal and sagittal brain slices from the mouse brain atlas illustrating the anatomical location of the nucleus accumbens. Scale bar = 2 mm. (C) Representative brain metabolite spectrum acquired using in vivo 16.4 T recorded with a PRESS sequence, as short as possible echo time (10 ms) and number of scans and repetition time that give reasonable SNR (NA 3072, TR 2000). (D) LCModel best fit of the brain metabolite spectrum in (C) with (E) Glu (red), Gln (green), GABA (blue) and NAA (purple) separated out and (F) the residual difference. Ala: Alanine; Cr: Creatine; GABA: γ-aminobutyric acid; Gln: Glutamine; Glu: Glutamate; GPC+PCh: Choline-containing compounds; Gua: Guanosine; Ins: myo-inositol; Lac: Lactate; NAA: N-acetylaspartate; PCr: Phosphocreatine; Tau: Taurine; VOI: Volume of interest. Figure adapted with permission from [10]. Anatomic representation of brain sections were adapted with permission from [146] © Elsevier.

Figure 3. Comparison of human and mouse brain with the striatum in field of view

The human brain is roughly an order of magnitude larger in linear size or three orders of magnitude larger in volume. (A) A typical voxel in human studies (white square, 2 × 2 × 2 cm) is placed in the area of the striatum. Scale bar = 2 cm. False color highlights the caudate nucleus (red), putamen (green) and nucleus accumbens (blue). The typical 8 ml volume voxel is larger than the whole mouse brain, and three orders of magnitude larger than (B) a typical voxel in the mouse brain (white square, 2 × 2 × 2 mm). Scale bar = 2 mm. False color highlights the dorsal medial striatum (analogue to the caudate nucleus; red), dorsal lateral striatum (analogue to the putamen; green) and nucleus accumbens (blue). VOI: Volume of interest.